New Insights in Treating LDL : PCSK9 Inhibitors

Robert A. Ketroser, M.D. Director Preventive Cardiology, Community Division University of Minnesota Heart Care DISCLOSURES

Relevant Financial Relationship(s) -Aventis and Regeneron Pharmaceuticals Inc: -Principal Investigator: Odyssey Study Off Label Usage None

Questions We Probably Won’t Get Answered Today • If 4 our of 5 people SUFFER from diarrhea…does that mean that one out of five enjoys it? • If one Synchronized Swimmer drowns, do the rest drown too? • If you ate both pasta and antipasto, would you still be hungry? • What ever happened to Preparations A through G? Questions We Probably Won’t Get Answered Today

• Is there another word for Synonym? • Why do they put Braille on the Drive-Through Bank Machines? • Whose cruel idea was it to put an “s” in the word “lisp”. • What hair color do they put on the driver’s license of bald men? • Lastly, why do banks charge a fee due to insufficient funds when they already know you’re broke? Objectives

1. Understand the recent AHA/ACC guidelines for cholesterol management. 2. Understand the ancillary treatment options for . 3. Be able to describe the purpose and function of PCSK9 Inhibitors. 4. Understand the Fourier and Odyssey Outcomes Trials. 5. Recognize Factors for higher risk in patients with clinical ASCVD.

Top 10 Take-Home Messages 2018 Cholesterol Guidelines

Top 10 Take Home Messages 1. In all individuals, emphasize a heart- healthy lifestyle across the life course.

A healthy lifestyle reduces atherosclerotic (ASCVD) risk at all ages. In younger individuals, healthy lifestyle can reduce development of risk factors and is the foundation of ASCVD risk reduction.

In young adults 20 to 39 years of age, an assessment of lifetime risk facilitates the clinician–patient risk discussion (see No. 6) and emphasizes intensive lifestyle efforts. In all age groups, lifestyle therapy is the primary intervention for metabolic syndrome. Top 10 Top 10 Take Home Messages

2. In patients with clinical ASCVD, reduce low- density cholesterol (LDL-C) with high-intensity therapy or maximally tolerated statin therapy.

The more LDL-C is reduced on statin therapy, the greater will be subsequent risk reduction.

Use a maximally tolerated statin to lower LDL-C levels by ≥50%.

The CTT (Cholesterol Treatment Trialists) meta-analysis of data from, 170,000 participants in 26 randomized trials suggests an approximate 22% reduction in CHD events with every 1 mmol/L (38 mg/dl) reduction in LDL-C.

The Lancet, Vol. 376, Issue:9753, 13-19 November, 2010, pages 1670-1681 Top 10 Top 10 Take Home Messages

3. In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider addition of nonstatins to statin therapy. • Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. • In very high-risk ASCVD patients, it is reasonable to add to maximally tolerated statin therapy when the LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L). • In patients at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable, although the long-term safety (>3 years) is uncertain and cost- effectiveness is low at mid-2018 list prices.

Patient Example #1

• R.G. - 65 y.o W. F. - Known CAD S/P NSTEMI 10 months earlier with PCI and DES to 80% LAD stenosis. L. Main 40% stenosis untreated. - FHX: Father with CABG age 64. Mother with NSTEM and PCI age 65. Sister and brother both with hyperlipidemia. - History of Hypertension - NMR Lipid Profile with increased LDL-C particles and lipids:

Patient #1 (continued)

• T. Chol 350 Triglycerides 96 HDL 49 LDL 282 • LDL GOAL < 70 mg/dl.

Patient #1 (continued)

• Treatment with 80 mg daily: discontinued due to myalgias. • Treatment with 40 mg daily: - LDL: 139 mg/dl • Zetia 10 mg daily added: - LDL: 105 mg/dl Treatment Choices??? PCSK9

• Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) • Regulates LDL receptor degradation. • Genetically determined decreases in LDL-C levels - 28% reduction in African Americans - 15% reduction in white subjects - Resulted in 88% and 47% reduction in CHD risk respectively compared to non-carriers.

CVD Prevention Role of Pharmacotherapy

Efficacy of Statin Therapy Unmet Need 1 2 3 12% 21% 70% Statin-associated Reductions in Vascular Mortality Statin-associated reduction in Major CV events for Patients with atherosclerotic CVD (ASCVD) on every 39% mg/dL reduction in LDL-C high/moderate-intensity who do not achieve LDL-C level <70 mg/dL

Recent meta-analyses of statin trials by the Cholesterol Treatment Trialists Collaboration (CTTC) have shown that statins reduce vascular mortality by 12% and major CV events by 21% per 1 mmol/L (38.67 mg/dL) of LDL-C reduction8 Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. A recent US database analysis suggested that 70% of patients with atherosclerotic CVD (ASCVD) on high/moderate-intensity statins do not achieve LDL-C level <70 mg/dL 1. Toth PP,etal J Med Econ. 2017: 20(6):555-564; 2. Sabatine MS, etal, Lancet Diabetes Endocrinol. 2017; 5(12): 941-950; 3. Steg P, etal. 67th American College of Cardiology Scientific Session and Expo; March 10-12 Orlando, FL.

Patient #1 (continued)

• (Praluent) started at 75 mg SC every 2 weeks • LDL cholesterol fell to 48 mg/dl (54% reduction) within 12 weeks. • Patient denies significant side effects with this three drug therapy. FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk

MS Sabatine, RP Giugliano, AC Keech, N Honarpour, SM Wasserman, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators

American College of Cardiology – 66th Annual Scientific Session Late-Breaking Clinical Trial March 17, 2017

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) – Chaperones LDL-R to destruction → ↑ circulating LDL-C – Loss-of-fxn genetic variants → ↑ LDL-R → ↓ LDL-C & ↓ risk of MI

Evolocumab – Fully human anti- PCSK9 mAb – ~60% ↓ LDL-C – Safe & well-tolerated in Ph 2 & 3 studies – Exploratory data suggested ↓ CV events

Sever P & Mackay J. Br J Cardiol 2014;21:91-3 An Academic Research Organization of Giugliano RP, et al. Lancet 2012;380:2007-17 Brigham and Women’s Hospital and Harvard Medical School Sabatine MS, et al. NEJM 2015;372:1500-9 Objectives

In patients with established cardiovascular disease on statin therapy: • Test whether the addition of evolocumab reduces the incidence of major cardiovascular events

• Examine the long-term safety & tolerability of evolocumab • Investigate the efficacy and safety of achieving unprecedented low levels of LDL-C

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Trial Design

27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)

Screening, Lipid Stabilization, and Placebo Run-in

High or moderate intensity statin therapy (± ezetimibe)

LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL

RANDOMIZED DOUBLE BLIND Evolocumab SC Placebo SC 140 mg Q2W or 420 mg QM Q2W or QM

Follow-up Q 12 weeks

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J 2016;173:94-101 Follow-up

Randomized 27,564 patients

Evolocumab Placebo (N=13,784) (N=13,780)

Follow-up median 26 months (IQR 22-30)

2907 patients experienced primary endpoint 1829 experienced key secondary endpoint

Premature perm. 5.6%/yr 5.8%/yr drug discontinuation

Withdrew consent 0.29%/yr 0.35%/yr

Lost to follow-up 5 patients 13 patients Ascertainment for primary endpoint was complete for 99.5% of potential patient-years of follow up An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School LDL Cholesterol

100 Placebo 90

80

70 59% mean reduction (95%CI 58-60), P<0.00001 60 Absolute reduction: 56 mg/dl (95%CI 55-57) 50

40

LDL CholesterolLDL (mg/dl) 30 Evolocumab 20 (median 30 mg/dl, IQR 19-46 mg/dl) 10

0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Primary Endpoint

16% Hazard ratio 0.85 14.6% 14% (95% CI, 0.79-0.92) P<0.0001 12.6% 12% Placebo Revasc 10% Cor 8% Evolocumab 6% CV Death, MI, Stroke, 4% Hosp for UA, for Hosp UA, or

2%

0% 0 6 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Key Secondary Endpoint

10% 9.9% 9% Hazard ratio 0.80 (95% CI, 0.73-0.88) 8% P<0.00001 7.9% Placebo 7%

6%

5%

4% Evolocumab

3% CV Death, MI, or Stroke 2%

1%

0% 0 6 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School More Intensive LDL-C Lowering & CV Death No clear benefit on CV mortality

# of CV Deaths Trial Year More Less HR (95% CI) Intensive Intensive Rx Arm Rx Arm PROVE-IT TIMI 22 2004 27 36 0.74 (0.45-1.22) A2Z 2004 86 111 0.76 (0.57-1.01) TNT 2005 101 127 0.80 (0.61-1.03) IDEAL 2005 223 218 1.03 (0.85-1.24) SEARCH 2010 565 572 0.99 (0.88-1.11) IMPROVE-IT 2015 538 537 1.00 (0.89-1.13) Summary 1540 1601 0.96 (0.90-1.03)

NEJM 2004;350:1495-504 JAMA 2004;292:1307-16 0.2 0.5 1 2 5 NEJM 2005;352:1425-35 More intensive Less intensive JAMA 2005;294:2437-45 Lancet 2010;376:1658-69 therapy better therapy better NEJM 2015;372:2387-97

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Landmark Analysis

8% 8% 16% RRR 25% RRR HR 0.84 (95%CI 0.74-0.96) HR 0.75 (95%CI 0.66-0.85) 6% P=0.008 6% P<0.00001

4% 4%

Placebo

CV Death, MI, Stroke 2% 2%

Evolocumab

0% 0% 0 3 6 9 12 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Summary for Evolocumab

• ↓ LDL-C by 59% – Consistent throughout duration of trial – Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl)

• ↓ CV outcomes in patients already on statin therapy – 15% ↓ broad primary endpoint; 20% ↓ CV death, MI, or stroke – Consistent benefit, incl. in those on high-intensity statin, low LDL-C – 25% reduction in CV death, MI, or stroke after 1st year – Long-term benefits consistent w/ statins per mmol/L ↓ LDL-C

• Safe and well-tolerated – Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo – Rates of EvoMab discontinuation low and no greater than pbo – No neutralizing developed

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Conclusions

In patients with known cardiovascular disease:

1. PCSK9 inhibition with evolocumab significantly & safely ↓ major cardiovascular events when added to statin therapy

2. Benefit was achieved with lowering LDL cholesterol well below current targets

An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Top 10 Top 10 Take Home Messages

4. In patients with severe primary hypercholesterolemia (LDL-C level ≥ 190 mg/dL[≥4.9 mmol/L]) without calculating 10-year ASCVD risk, begin high-intensity statin therapy without calculating 10-year ASCVD risk.

•If the LDL-C level remains ≥100 mg/dL (≥2.6 mmol/L), adding ezetimibe is reasonable

• If the LDL-C level on statin plus ezetimibe remains ≥100 mg/dL (≥2.6 mmol/L) & the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered, although the long-term safety (>3 years) is uncertain and economic value is low at mid-2018 list prices. Top 10 Top 10 Take Home Messages 5. In patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk.

In patients with diabetes mellitus at higher risk, especially those with multiple risk factors or those 50 to 75 years of age, it is reasonable to use a high-intensity statin to reduce the LDL-C level by ≥50%. Patient #2

• N.B. 59 y.o.w.f. • No previous ASVD • + Type II AODM; HbA1C=6.3% • + FHX - Father with MI in 50’s and CABG age 70. - Brother with MI age 50. • + HTN • CT Calcium Score of 55 in 2015 (25-50th %).

N.B. (patient #2 cont.)

• Lipid Profile in 2015: Total Cholesterol: 348 Triglycerides: 105 HDL: 70 LDL: 257 Lipoprotein A (Lp(a)): 186.4 (Normal <50 mg/dl). Factors for Highest Risk in Patients with Clinical ASCVD N.B. (patient #2)

• Patient started on atorvastatin with LFTs after 3 months: - ALT: 247 (Nl=0-32) - AST: 194 (Nl=0-55) - Statin discontinued and LFTs normalized within 3 months. - Zetia started 10 mg daily - LDL after 3 months: 202

N.B. (patient #2)

• Evolocumab (Repatha) started at 140 mg SC q 14 days. • Lipid Profile 11/2/18 - Total Cholesterol: 215 Triglycerides: 128 HDL: 70 LDL: 119

Cost Effectiveness of Alirocumab in ODYSSEY OUTCOMES

• The higher the baseline LDL-C in patients, the higher the value of alirocumab appeared to be. • Cost-effectiveness was greater in patients with baseline LDL-C > 100 mg/dL relative to the overall ITT population. • Cost-effectiveness was lower in patients with baseline LDL-C < 100 mg/dL relative to the overall ITT population. • Alirocumab may offer good value in patients with a history of ACS and LDL-C > 100 mg/dL despite maximally tolerated statin therapy based on both absolute clinical benefit and cost-effectiveness. Key Take Home Messages

• Patients with the highest risk for CV events are positioned to gain the greatest benefit from the addition of non-statin therapy. • Data from long-term trials with PCSK9 Inhibitors have shown benefits on both LDL levels and CV events as well as good safety profiles. • In comparing FOURIER Trial and ODYSSEY OUTCOMES, - 20-25% reduction in MI and acute Stroke in both studies. - No change in Mortality in Fourier Trial (shorter F/U) whereas there was a change in mortality in 2.5 years (curves diverging) in ODYSSEY OUTCOMES (>3 year F/U). PCSK9 Inhibitor Indications

• Patients with heterozygous Familial Hypercholesterolemia (FH). • Individuals with ASCVD, who require additional LDL-C lowering. • Patients intolerant to statin therapy. • Evolocumab approved for homozygous FH based on the TESLA trial (18-44% reduction LDL-C with 420 mg monthly injections in patients with at least 2% of functioning LDL receptors). • Reduction of ASCVD events when added to a statin. Thank you for attending The Women’s Heart Conference! Lp(a)

• Analysis showed that CHD risk was directly proportional to the absolute change in plasma lipoprotein(a) mass concentration. For each 10 mg/dL lower genetically estimated lipoprotein(a) levels, predicted by the LPA genetic risk score, there was a 5.8% lower CHD risk (95% confidence interval 4.9% to 6.7%). For comparison, each 10 mg/dL lower LDL cholesterol value predicted using an LDL genetic score was associated with a 14.5% lower CHD risk (95% confidence interval 10.7% to 18.2%). This suggests that 1 mg/dL difference in LDL cholesterol has the same effect on CHD risk as a 2.63 mg/dL difference in lipoprotein(a) concentration. • In other words, a 1 mmol/L (38.7 mg/dL) difference in LDL cholesterol has the same effect as about 100 mg/dL difference in lipoprotein(a). • Ference BA, et al. European Atherosclerosis Society, May 5-8, 2018 Lisbon, Portugal. Late Breaking insight into Lioprotein function session. Lp(a) Take Home Message “ To get the same benefit of lowering LDL 40 mg/dl= 2 Risk 20%, You must get more Lp(a) lowering for same effect (closer to 100mg/dl) 2 1/2 times LDL.” In FOURIER Study: -Increased Lp(a)=Increased Events Risk Reduction is reduced with Lp(a) lowering -Need very high Lp(a) levels (125 mg/dl) to achieve benefits with Lp(a) lowering. Lp(a)

25% Lp(a) reduction with PCSK9 Inhibitor but not with statin.